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Biomedical subjects

W J Scott

Publications and source records attributed to W J Scott.

At least 19 recordsLinked to original sources
PubMed1992

Dominant mutation of the murine Hox-2.2 gene results in developmental abnormalities.

Genes carrying the homeobox were originally identified in Drosophila, in which they are now known to play key roles in establishing segmentation patterns and in determining segment identities. A number of genes with striking homology to the Drosophila homeobox genes have now been found in the mouse genome, and mutational analysis is beginning to shed light on their function in mammalian development. To understand better the developmental significance of the murine Hox-2.2 gene, we have generated gain of function mutants by using the chicken beta-actin promoter to drive ubiquitous expression in transgenic mice. The resulting Hox-2.2 misexpression produces early postnatal lethality as well as craniofacial and axial skeletal perturbations that include open eyes at birth, cleft palate, micrognathia, microtia, skull bone deficiencies, and structural and positional alterations in the vertebral column. We repeatedly observe complete or partial absence of the supraoccipital bone and malformations of the exoccipital and the basioccipital bones. These results suggests a role for the Hox-2.2 gene in specifying positional identity along the anterior-posterior axis.

Abnormalities, Multiple↗
PubMed1992

Abnormalities in ureter and kidney development in mice given acetazolamide-amiloride or dimethadione (DMO) during embryogenesis.

These experiments more accurately define the effects of the combination acetazolamide-amiloride or a single dose of dimethadione (DMO), the active metabolite of trimethadione, on the development of the ureter. When acetazolamide-amiloride was administered in C57BL/6NCrlBR mice on day 9, 9.5, or 10 of gestation (plug = day 0) a second ureter was formed, anterior to the original ureter, inducing a second kidney. The second ureter then fails to make a connection with the developing bladder and remains attached to the mesonephric duct. The mesonephric duct becomes the vas deferens in the male and deteriorates completely in the female leading to either a restricted ureter or a blocked ureter depending on the sex of the fetus. Administration of a single dose of DMO between gestational day 9 and 10.3 produced both renal agenesis and ureters of varying lengths. Some ureters were of normal length with a tuft of one or two nephrons at their tip, while others were one half or one quarter of their normal length. In some instances the ureter was completely absent. The reason for this strong effect on the ureter is unknown.

Abnormalities, Drug-Induced↗
PubMed1992

Murine teratology and pharmacokinetics of the enantiomers of sodium 2-ethylhexanoate.

A mouse model for the induction of exencephaly with sodium (+/-)-2-ethylhexanoate has been developed using multiple administration regimes. With three consecutive administrations at one-half-day intervals, the most sensitive time to induce exencephaly was Gestational Days 8-9. Using the racemic substance it was determined that the SWV strain was more sensitive to the induction of exencephaly than the C57BL/6NCrlBR strain. The enantiomers of 2-ethylhexanoic acid were separated via preparative HPLC to greater than 99.8% optical purity, and greater than 99% purity according to a gas chromatographic analysis. It was demonstrated that the (R)-enantiomer is a more potent teratogen than the (S)-enantiomer for the induction of exencephaly as well as malformations of other organ systems. Pharmacokinetic analyses for each of the enantiomers were performed in maternal plasma, maternal muscle, and embryo. The pharmacokinetics showed that the peak concentration (Cmax) for both enantiomers in the three compartments was approximately equivalent and was attained within 15 min following the third administration. The area under the concentration versus time curve values for the two enantiomers were approximately 10% higher for the (R)-antipode because of a slightly slower elimination of this compound. There was negligible (or no) racemization of the two enantiomers in the biological samples. The results suggest that teratologic differences in the enantiomers of sodium 2-ethylhexanoate are not due to differences in the concentrations of these antipodes in the embryo, but more likely result from the specific interaction of the enantiomers with chiral molecules in the embryo.

Abnormalities, Drug-Induced↗
PubMed1992

Efficacy, complications, and cost of a comprehensive blood conservation program for cardiac operations.

We reviewed blood use in 118 consecutive patients who underwent primary, elective cardiac operations in 1989. In June 1989 we initiated a blood conservation program that included attempts to limit preoperative aspirin use, intraoperative phlebotomy and hemodilution, use of a cell conservation device (Electromedics, Inc., Englewood, Colo.) to concentrate residual oxygenator contents, reinfusion of chest drainage, and acceptance of a minimum hemoglobin level of 8.0 gm/dl in stable patients. Patient characteristics were similar for patients operated on both before (n = 58) and after (n = 60) initiation of the blood conservation program, except for age and preoperative aspirin use (both greater in postconservation patients). Fewer blood products were transfused (5.8 +/- 5.7 units per patient before conservation versus 4.0 +/- 7.4 units per patient after conservation; p = 0.005). More complete data were available for 82 patients (40 patients before conservation and 42 after conservation). In the postconservation patients, 20 of 42 had 575 +/- 140 ml of blood withdrawn before cardiopulmonary bypass and reinfused afterward, 26 of 42 had 806 +/- 376 ml of blood processed with the cell conservation device returned, and 21 of 42 patients had an average of 287 +/- 127 ml of chest drainage reinfused. Chest tube drainage, postoperative hematologic parameters, and the prevalence of complications were not significantly different between groups. Stepwise linear regression analysis identified intraoperative withdrawal of blood before cardiopulmonary bypass, bypass duration, and preoperative hematocrit value as predictors of blood use. Intraoperative withdrawal of blood before cardiopulmonary bypass is an important conservation measure, and its use should be expanded.

Aspirin↗
PubMed1991

A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis.

The c-myb proto-oncogene encodes a sequence-specific DNA-binding protein. To better understand its normal biological function, we have altered the c-myb gene by homologous recombination in mouse embryonic stem cells. Resulting homozygous c-myb mutant mice displayed an interesting phenotype. At day 13 of gestation these mice appeared normal, suggesting that c-myb is not essential for early development. By day 15, however, the mutant mice were severely anemic. Analysis indicated that embryonic erythropoiesis, which occurs in the yolk sac, was not impaired by the c-myb alteration. Adult-type erythropoiesis, which first takes place in the fetal liver, was greatly diminished in c-myb mutants, however. Additional hematopoietic lineages were similarly affected. These results are compatible with a role for c-myb in maintaining the proliferative state of hematopoietic progenitor cells.

Animals↗
PubMed1991

Transplacental distribution of weak acids in mice: accumulation in compartments of high pH.

The transplacental distribution of three weak acids was measured in mice on gestational day 11. The ratio of drug concentration in maternal, embryonic, and extraembryonic compartments compared to maternal plasma followed a consistent hierarchy such that amniotic fluid greater than or equal to exocoelomic fluid greater than embryo greater than embryo plasma greater than maternal skeletal muscle. This distribution pattern correlates well with pH in these compartments and suggests that pH gradients between compartments are an influential factor in determining weak acid drug disposition during pregnancy.

Acids↗
PubMed1991

The effect of administration time on malformations induced by three anticonvulsant agents in C57BL/6J mice with emphasis on forelimb ectrodactyly.

Exposure of C57BL/6J mice to three anticonvulsant derivatives, namely, dimethadione, sodium valproate, and sodium diphenylhydantoin, each induced postaxial forelimb ectrodactyly. The agents were administered at gestational days 9, 9 1/3, 9 2/3, and 10. It was determined that administration at day 9 2/3 induced the highest percentage of forelimb ectrodactyly for each of the three agents. The forelimb ectrodactyly response in the C57BL/6J strain was compared with the A/J strain (Collins et al., Teratology, 41:61-70, 1990); it was found that the C57BL/6J strain was more sensitive to dimethadione and the A/J strain was more sensitive to diphenylhydantoin and sodium valproate. The position of vertebral defects induced by sodium valproate correlated with the time of drug administration. The overall syndrome of malformations induced by the three anticonvulsant agents was relatively similar in the two mouse strains and differed between each of the anticonvulsant agents.

Abnormalities, Drug-Induced↗
PubMed1990

Phenotypic characterization of the transgenic mouse insertional mutation, legless.

In this report, we describe the dysmorphologic phenotype associated with the transgenic insertional mutation legless. This autosomal recessive, perinatally lethal mutation results in an interesting pleiotropic array of congenital malformations. The phenotype of the legless mutation in homozygous perinatal mutants is compared to wild-type nontransgenic and heterozygous siblings. Skeletal, craniofacial, and visceral malformations are characterized. We have observed by skeletal analysis a consistent loss of distal hindlimb structures, as well as the loss of distal forelimb structures with a predilection for the preaxial side of the developing forelimb. Craniofacial malformations commonly observed appear to represent a range of severity of affect, with the mildest manifestation evident as apparently shallow lateral clefts of the upper lip and mild midfacial clefts accompanied by clefts of the secondary palate. At the severe end of the spectrum, the midline clefts of the face (and secondary palate) are very wide, with obvious accompanying frontonasal encephaloceles and overt lateral clefts of the upper lip. Examination of the mutant brain has demonstrated marked defects in the anterior structures, particularly the olfactory lobes and cerebrum, in greater than 90% of the brains studied. Observation of the internal viscera has identified transposition of thoracic and abdominal organs in approximately 50% of the mutant offspring. The limb, head, and visceral defects were not observed in the wild-type nontransgenic or heterozygous siblings. Transgenic insertional mutations leading to congenital malformations are useful because the transgene sequence may serve as a tag to facilitate molecular retrieval. Analysis of the flanking DNA sequences will allow the identification of the interrupted gene. A complete description of the mutant phenotype will assist in the understanding of this genetic locus.

Animals↗
PubMed1990

Induction of postaxial forelimb ectrodactyly with anticonvulsant agents in A/J mice.

Exposure of A/J mice on day 9.5 of gestation to the derivatives of three acidic anticonvulsant agents, namely dimethadione, sodium valproate, and sodium diphenylhydantoin, each induced postaxial forelimb ectrodactyly predominantly of the right side. This specific malformation has previously been associated with the administration of acetazolamide to rodents; however, several agents can induce this same defect including other carbonic anhydrase inhibitors, carbon dioxide, cadmium, ethanol, ammonium chloride, and 13-cis retinoic acid. The relative potency of the three agents indicates no direct relationship to the pKa of the acid. Other than ectrodactyly, each of the anticonvulsant agents induced a compound-specific spectrum of malformations despite the uniform administration time. This finding suggests that these agents are capable of acting via different mechanisms or by the differential spatial and temporal dynamics of a common mechanism.

Abnormalities, Drug-Induced↗
PubMed1990

Ethanol-induced limb defects in mice: effect of strain and Ro15-4513.

It is now thought that ethanol exerts many of its behavioral effects in the CNS by interaction with the gamma-aminobutyric acid (GABA) receptor, and it has been shown that the benzodiazepine reverse agonist Ro15-4513 reverses some of the CNS effects produced by ethanol. The hypothesis was tested that ethanol exerts its teratogenic effects through interaction with a putative embryonic GABA receptor by determining whether Ro15-4513 reverses ethanol-induced forelimb ectrodactyly in C57BL/6 mice. First, pregnant C57BL/6 dams were injected twice i.p. with ethanol (2.9 g/kg body weight, 4 hr apart) on day 10 of gestation: 49% of the fetuses were resorbed or dead and 46% of the survivors showed forelimb ectrodactyly. In contrast, when SWV mice were treated with ethanol, embryolethality was only 11.9% and no forelimb ectrodactyly was observed. In a second experiment, when ethanol (2.6 g/kg x 2) was administered to C57BL/6 mice, 34% resorptions and 31% forelimb ectrodactyly were observed. Ectrodactyly induced by ethanol was primarily of the forelimb and exclusively postaxial. Ethanol produced an unusual forelimb defect in a small number of instances where there was a postaxial autopod reduction defect coupled with a preaxial zeugopod reduction defect. Ro15-4513 administered alone (50 mg/kg x 2) was neither embryolethal nor teratogenic in C57BL/6 mice. To attempt to reverse the teratogenic effect of ethanol, dams that were injected 5 min before each ethanol administration with Ro15-4513 (0.5, 1, 2.5, 5, 10 mg/kg twice) showed no significant change in frequency of forelimb ectrodactyly compared to embryos treated with ethanol alone. However, resorptions increased significantly to 77% and 62% with the 5 and 10 mg/kg doses of Ro15-4513. Thus there appears to be an embryolethal interaction of Ro15-4513 with ethanol. Nevertheless, since Ro15-4513 did not reverse the teratogenic effect induced by ethanol, these results do not support the hypothesis that the teratogenic mechanism of ethanol is mediated through a putative embryonic GABA receptor.

Abnormalities, Drug-Induced↗
PubMed1990

Blood conservation in cardiac surgery.

We reviewed current blood conservation techniques and their use in cardiac surgery. Avoidance of aspirin preoperatively is an important blood conservation measure. Patients scheduled for an elective operation should participate in autologous predonation programs. With careful monitoring, patients with major coronary artery disease can safely donate blood preoperatively. Intraoperative processing of blood withdrawn before cardiopulmonary bypass provides autologous platelet-rich plasma for infusion after reversal of heparin sodium. Blood collected from the field during operation and blood remaining in the oxygenator after bypass can also be processed to yield washed and concentrated red blood cells for reinfusion. Randomized, prospective studies document that postoperative autotransfusion is both safe and effective in reducing homologous blood use. Aprotinin reduces plasma protein activation and platelet damage during bypass. The integration of available blood conservation techniques into a comprehensive program combined with careful consideration of the indications for transfusion may allow more patients to avoid transfusion entirely.

Blood Loss, Surgical↗
PubMed1990

Reduction of embryonic intracellular pH: a potential mechanism of acetazolamide-induced limb malformations.

The effects of acetazolamide on the developing rodent limb bud were postulated to result from a reduction of intracellular pH (pHi). Embryonic intracellular pH was calculated from transplacental distribution of the weak acid, 5,5'-dimethyloxazolidine-2,4-dione, in teratogenically sensitive (C57BL/6) and resistant (SWV) inbred mice. pHi was reduced by acetazolamide treatment in C57 embryos and limb buds but not in SWV samples. Acetazolamide teratogenesis can be exacerbated by coadministration of amiloride, presumably through inhibition of Na+/H+ exchange attributable to the latter agent. pHi reduction after such treatment was more profound than after acetazolamide alone, providing further support for the central hypothesis. pH was also reduced in other embryonic (embryo plasma) and extraembryonic compartments (exocoelomic fluid, amniotic fluid). pH changes in these compartments could also lead or contribute to abnormal development.

Abnormalities, Drug-Induced↗
PubMed1989

Teratologic potential of 2-methoxyethanol and transplacental distribution of its metabolite, 2-methoxyacetic acid, in non-human primates.

The embryotoxic effects of 2-methoxyethanol (2-ME) were studied in non-human primates to better assess the risk for women of child-bearing age exposed to this agent. Macaca fascicularis females were treated daily throughout the organogenetic phase of pregnancy (days 20-45) by gavage and the fetuses collected at day 100 by Caesarean section. At the highest dose (0.47 mmole/kg), all eight pregnancies ended in death of the embryo. One of these dead embryos was abnormal, missing a digit on each forelimb. At the middle dose (0.32 mmole/kg), three of 10 pregnancies ended in embryonic death, presumably due to 2-ME exposure and three of 13 pregnancies met a similar fate at the low dose (0.16 mmole/kg). In each of these two groups, an additional pregnancy was lost to abortion, but both were thought to be spontaneous, which usually occurs in 10-20% of untreated macaque pregnancies. These results indicate that 2-ME is a potent toxin to the developing primate embryo and thereby furthers the concern about exposure of pregnant women to this agent, although maternal toxicity was evident in nearly all treated pregnancies and was especially severe in the high-dosage animals. Distribution of the major metabolite of 2-ME, 2-methoxyacetic acid (2-MAA), indicated a long half-life (ca. 20 h), resulting in accumulation of metabolite in maternal serum after repeated daily dosing. Transplacental studies revealed uniform distribution in the embryo and extraembryonic fluids at a concentration similar to that in maternal serum. The yolk sac, on the other hand, accumulated a very high concentration of 2-MAA, but the embryotoxic significance of this observation is unknown.

Acetates↗
PubMed1989

Embryo-maternal distribution of basic compounds in the CD-1 mouse: doxylamine and nicotine.

The intracellular pH of the early postimplantation rodent embryo (pHi) is alkaline with respect to the corresponding plasma of the pregnant dam. This transplacental pH gradient is of considerable importance in the accumulation of teratogenic weak acids by the embryo. The importance of pH in the partitioning of basic drugs across the early mammalian placenta has not been investigated. Theoretically, the maternal plasma should retain a higher concentration of basic drugs than the embryo due to a greater degree of drug ionization in the more acidic plasma. To explore the significance of pH partitioning upon the transplacental distribution of basic compounds, two bases, doxylamine and nicotine, were administered to pregnant CD-1 mice during early organogenesis. The maternal plasma and embryonic concentrations of the bases were measured and the resulting embryo/maternal plasma (E/P) ratio was calculated and compared to the ratio predicted by the Henderson-Hasselbalch equation. Following ip injection of nicotine on Day 9 of gestation, the E/P ratio was significantly greater than the predicted ratio 10 min after injection and continued to rise for 3 hr. For doxylamine succinate administered by oral gavage on Day 9 or 10, the E/P ratio was also significantly greater than the ratio predicted from the pH gradient. Our results indicate that the partitioning of these basic compounds between the maternal plasma and the early postimplantation rodent embryo is not a consequence of the pH gradient between the two compartments alone.

Animals↗
PubMed1989

Advanced three-dimensional evaluation of acetabular trauma: volumetric image processing.

Volumetric image processing is a new approach to generating simulated three-dimensional images from transaxial CT data. The major advantages compared to conventional surface-rendering 3D technique include: preservation of every pixel of CT data for increased accuracy of rendered image; tissue layer translucency allowing appreciation of multiple tissue layers on each image; simulation of real-time rotation in varying axes for optimal appreciation of abnormalities; and a high-speed, high-capacity computer setup which generates high-quality images rapidly, giving the system sufficient flexibility for these complicated functions while remaining user friendly and fast.

Accidents, Traffic↗
PubMed1989

Decreasing pH of rat embryos and fluids estimated by transplacental distribution of DMO.

Utilizing the transplacental distribution of a weak acid, 5,5-dimethyloxazolidine-2,4-dione (DMO), we have measured the pH of cells within the rat embryo in vivo on days 11.5-14 of gestation. This is a period of rapid organogenesis in this species when the cells of many organ systems begin to change from a proliferative mode into a differentiated state. We found that intracellular pH of the day 11.5 rat embryo is 7.47 +/- 0.03 and decreases steadily to day 14 at which time it reaches 7.11 +/- 0.03. Because there is a concomitant fall in proliferative rate over this span of development, we suggest this correlation to be additional evidence of an association between proliferation and alkalinization of the cell interior. A number of other compartments including embryo plasma, amniotic fluid, exocoelomic fluid, and yolk sac have a decreasing concentration of DMO as development advances, indicative of a steadily declining pH. These changes could have developmental and pharmacokinetic implications.

Animals↗
PubMed1989

Biliary stone disease in adults with cystic fibrosis.

A 27-year-old woman with cystic fibrosis had a 6-month history of fatty food intolerance and biliary colic. Ultrasonographic studies confirmed the presence of gallstones. A cholecystectomy and appendectomy were performed. An intraoperative cholangiogram showed anomalous drainage of the cystic duct into an accessory right hepatic duct. Patients with cystic fibrosis now commonly survive into adulthood and are at high risk for the development of cholelithiasis. The diagnosis may be obscured by other common gastrointestinal complications of cystic fibrosis. Optimal surgical management includes meticulous preoperative and postoperative pulmonary care. The surgeon must also have a thorough knowledge of the biliary tract anomalies that have been described in patients with cystic fibrosis.

Adult↗